title: Lentivirus-mediated shRNA targeting of cyclin D1 enhances the chemosensitivity of human gastric cancer to 5-fluorouracil.
abstract: Gastric cancer is one of the major public health problems. Despite new chemotherapeutic treatments, the prognosis of gastric cancer remains poor. 5-Fluorouracil (5-FU) is used as a standard chemotherapy drug in gastric cancer. However, 5-FU resistance develops frequently and is a main cause of chemotherapy failure in human gastric cancer. Overexpression of cyclin D1 is related to rapid cell growth, a poor prognosis and increased chemoresistance in several types of cancers. In this study, we investigated whether treatment of gastric cancer cells with shRNA targeting cyclin D1 (ShCCND1) or 5-FU, alone or in combination, influences the activation of phosphorylated AKT (pAKT) and pNFκB, which are markers that are increased in 5-FU chemoresistance. We also investigated the effect of combined treatment with ShCCND1 and 5-FU on cell growth and chemosensitivity to 5-FU in the gastric cancer cell line AGS. The data showed that ShCCND1-mediated cyclin D1 downregulation in AGS cells significantly inhibited cell proliferation, cell mobility and clonogenicity. In addition, combined treatment with ShCCND1 and 5-FU significantly decreased the survival rate of AGS cells, compared to single-treatment with either agent. These results demonstrated that ShCCND1 increases 5-FU chemosensitivity, a conclusion that is also supported by the concomitant reduction in expression of pAKT and pNFκB, increase of G1 arrest and induction of apoptosis. Taken together, these data provide further evidence that therapeutic strategies targeting cyclin D1 may have the dual advantage of suppressing the growth of cancer cells, while enhancing their chemosensitivity.
authors.affiliation: Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Seo
authors.forename: Eui-Suk
authors.initials: ES
authors.lastname: Jeong
authors.forename: Kyoung-Sun
authors.initials: KS
authors.lastname: Lee
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Heo
authors.forename: Dong-Gu
authors.initials: DG
authors.lastname: Jeong
authors.forename: Yang-Kyu
authors.initials: YK
authors.lastname: Choi
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; C530104:CCND1 protein, human; D016328:NF-kappa B; D034741:RNA, Small Interfering; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil